It is now widely know that a number of undesirable physiological conditions are androgen-mediated and are dependent on 5.alpha.-dihydrotestosterone (DHT). Such conditions include benign prostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenic alopecia, hirsutism and prostate cancer. It has been demonstrated that inhibitors of 5.alpha.-reductase (5AR) block the formation of DHT, because 5AR mediates the conversion of testosterone to the more potent androgen DHT in various target organs. Finasteride, a 5AR inhibitor, is now in the pharmaceutical marketplace and is approved for the treatment of benign prostatic hyperplasia. Mocellini et al., The Prostate, 22, 291-99 (1993).
Recently it has been found that there are at least two 5AR isozymes in the human, Anderson et al., Proc. Natl. Acad. Sci. USA, 87, 3640-44 (1990); Andersson et al., Nature, and Type II, exhibit differences in their biochemical properties, genetics and pharmacology. Both isozymes are now the subject of considerable research and it has been found that Type I is more prevalent in the scalp and is more involved in conditions such as androgenic alopecia, and that Type II is more prevalent in the prostate. In prostate, Type I is exclusive to the epithelial compartment in normal, benign hyperplastic and cancerous cells, and the Type II isoform predominates in the fibromuscular stroma.
The present invention provides a series of new compounds which are effective inhibitors of 5AR; many of the compounds are effective inhibitors of both of the 5AR isozymes.